Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160, Bizkaia, Spain.
Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
J Hepatol. 2021 Jul;75(1):34-45. doi: 10.1016/j.jhep.2021.01.043. Epub 2021 Feb 9.
BACKGROUND & AIMS: Perturbations of intracellular magnesium (Mg) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH).
Serum Mg levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine.
Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs.
CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH.
Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.
细胞内镁（Mg）稳态的紊乱与细胞生理功能有关。细胞周期蛋白 M 家族（CNNM）在 Mg 跨细胞膜转运中发挥关键作用。本研究旨在阐明 CNNM4 在非酒精性脂肪性肝炎（NASH）发病机制中的作用。
在临床样本中检测血清 Mg 水平和肝 CNNM4 表达。在蛋氨酸和胆碱缺乏的条件下培养原代肝细胞。采用 0.1%蛋氨酸和胆碱缺乏饮食或胆碱缺乏高脂饮食诱导体内 NASH 动物模型。采用 DharmaFECT 体外、Invivofectamine®或半乳糖胺偶联物体内沉默 Cnnm4，检测其对 NASH 动物模型的影响。
NASH 患者表现出肝 CNNM4 过表达和血清 Mg 水平紊乱。沉默 Cnnm4 可改善 NASH 动物模型的肝脂质蓄积、炎症和纤维化。机制上，肝细胞中 CNNM4 沉默可诱导细胞内 Mg 蓄积、减少内质网应激，增加微粒体甘油三酯转移蛋白活性，从而通过增加 VLDLs 的分泌促进肝脏脂质清除。
CNNM4 在 NASH 患者中过度表达，负责调节 Mg 转运。肝 CNNM4 是治疗 NASH 的一个有前途的治疗靶点。
细胞周期蛋白 M4（CNNM4）在非酒精性脂肪性肝炎（NASH）中过度表达，促进镁从肝脏中输出。特异性沉默 Cnnm4 可通过减少内质网应激和促进微粒体甘油三酯转移蛋白的活性来改善 NASH。
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